ABSTRACT This proposal focuses on the role of in utero exposure to maternal autoimmunity in determining neurodevelopmental outcomes of the offspring. Our preliminary data provide strong support for the hypothesis that anti-brain antibodies in mothers have a contributory role in the development of autism spectrum disorders (ASD). We focus particularly on ASD, in part because the incidence of this disorder has increased dramatically over the past few decades. While many environmental triggers have been suggested, growing evidence indicates roles for maternal autoimmunity and maternal immune activation. There is evidence from animal studies that exposure in utero to maternal anti-brain antibodies plays a role in disease pathogenesis. When serum or purified IgG from women with brain-reactive antibodies and a child with ASD are administered to pregnant mice or monkeys, the offspring exhibit abnormalities in social behavior, increased anxiety or increased motor activity. In cross sectional studies, we have shown that women with a child with ASD are 4-5 times more likely to have brain-reactive serology than unselected women of child-bearing age. These antibodies are enriched in women with autoimmunity, and autoimmunity in a mother has been shown to predispose to ASD outcome. Despite these intriguing observations, there is a lack of prospective data in humans showing a relationship between autoimmunity and/or inflammation during gestation and the presence of neurodevelopmental abnormalities in offspring. This project will investigate a prospective cohort to address this issue by enriching for mothers who have evidence of autoimmunity, and comparing the incidence of neurodevelopmental disorders in their children to the children of control mothers without evidence of autoimmunity. In specific aim 1, we will test the hypothesis that clinical or subclinical autoimmunity in the mother at the time of pregnancy predisposes to a child with ASD. We will monitor ASD related outcomes in a cohort of 4,500 mothers who are enriched for the presence of autoimmune disease. In specific aim 2, we will test the hypothesis that the presence of maternal anti-brain antibodies during pregnancy predisposes to a greater risk of a child with ASD or neurodevelopmental problems. In specific aim 3, we will test the hypothesis that maternal immune activation or increased cytokine levels at during pregnancy predisposes to ASD in the child. We will follow cytokine levels and modular patterns of maternal whole blood gene expression in the second and third trimesters in order to assess the contribution of maternal immune and inflammatory factors to ASD-related phenotypes in offspring. Prospective data supporting a role for intrauterine environment on risk for ASD will fundamentally alter our understanding of ASD pathogenesis and will lead directly to potential diagnostics as well as new approaches to disease prevention.